Penn Researchers Demonstrate Ability
of New Therapy to
Treat Patients With Severely Elevated Cholesterol LevelsNew England Journal of Medicine Publishes Report of New Therapeutic
Approach
That Has Implications for People With High Cholesterol

"Our study shows that targeted inhibition of the microsomaltriglyceride
transfer protein (MTP) is highly effective in reducing cholesterol levels
in these very high risk patients,” stated Daniel
J. Rader, MD, Director of Preventive
Cardiology and the Clinical and Smilow Center for Translational Research (SCTR) at Penn,
and principal investigator of this study. “Furthermore, there are
many other patients who have cholesterol levels that are difficult to
treat or who are not tolerant to treatment with statins.
New therapies are required for these patients as well, and it is possible
that after further research MTP inhibition could eventually be used for
such patients.”

Genetic defects in MTP lead to profoundly low levels of LDL. Using this
information, Bristol-Myers
Squibb began to search for inhibitors of this protein and discovered
the study drug, originally known as BMS-201038. Bristol-Myers Squibb then
donated it to Penn for use in clinical trials in patients with severe
cholesterol problems. Rader and his team at Penn designed and carried
out the current study in homozygous FH patients with support from the
Doris Duke Charitable Foundation.
Due to the success in this study, Penn has licensed the drug to Aegerion
Pharmaceuticals, Inc. for further development as AEGR-733.

Patients who suffer from homozygous FH typically respond poorly to standard
drug therapy and have a very high risk of premature cardiovascular
disease. Homozygous FH is caused by loss-of-function mutations in
both alleles
of the LDL receptor gene. It is a rare form of hypercholesterolemia
affecting approximately one in every million people. Patients with this
disorder typically have plasma cholesterol levels of more than 500 mg
per deciliter. If untreated, patients develop cardiovascular disease before
they are 20 years old and generally do not live past the age of 30. Because
existing cholesterol lowering drugs are relatively ineffective in this
patient population, new therapies to reduce LDL levels are needed.

In this study, researchers conducted a dose-escalation study to examine
the safety, tolerability and effects on lipid
levels of an inhibitor of MTP in six patients with homozygous FH. Patients
received the MTP inhibitor at four different doses, each for four weeks,
and returned for a final visit after an additional four-week drug washout
period. Analysis of lipid levels, safety laboratory analyses, and magnetic
resonance imaging of the liver for hepatic
fat content were performed throughout the study. All patients tolerated
titration
to the highest dose studied. In addition to the 51% reduction in LDL cholesterol,
treatment at this dose also decreased total cholesterol levels by 58%,
triglyceride levels by 65% and apolipoprotein
B levels by 56% from baseline. In contrast to statin drugs, which
have relatively little effect on cholesterol levels in homozygous FH patients,
the MTP inhibitor was shown to reduce the liver’s ability to produce
LDL. The most notable adverse events in the study were loose stools and
elevation of liver transaminase
levels and accumulation of hepatic fat in some but not all of the patients
studied.

Rader concluded, “Although our study establishes proof of concept,
a longer-term study in more patients will be required to determine the
benefits and risks of this approach as a potential new therapy for homozygous
familial hypercholesterolemia." Marina
Cuchel, MD, PhD, a co-investigator in this study at Penn,
is now the principal investigator of a Phase
III study for this compound in homozygous FH patients that is funded
by the US Food and
Drug Administration Orphan Drug program and planned for later this
year.

Rader points out that this study is a superb example of “translational
research” in which discoveries in basic science are “translated”
into use in humans for the development of novel therapies. Rader is an
internationally recognized leader in translational research in the areas
of cholesterol metabolism and heart disease prevention. Penn recently
created a new Cardiovascular Institute
that is charged with promoting translational research in the diagnosis,
treatment, and prevention of cardiovascular disease. Additionally, Penn
was recently awarded a large National
Institutes of Health grant to foster the further development of translational
research under the auspices of the newly created Institute
for Translational Medicine and Therapeutics.

Editor’s Notes: Daniel J. Rader, MD, receives lecture
fees, consulting fees, and grant support from Bristol Myers-Squibb, as
well as from other companies that manufacture lipid-lowering drugs, and
has equity interest in Aegerion Pharmaceuticals, which holds the license
to develop BMS-201038.

LeAnne Bloedon serves as a consultant for Aegerion Pharmaceuticals.

Philippe O. Szapary, MD, is an employee of and has equity interest in
Wyeth.

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